Nicotine abuse is one of the major health problems in the world today. The use of nicotine via cigarette smoking forms lifelong memories that are recalled in response to environmental cues associated with previous nicotine use. This recall increases drug craving and is a factor for the continued use of nicotine. Understanding how the long-lasting memories are formed may aid in developing therapies for preventing the relapse, and thereby promote smoking cessation. Increasing evidence indicates that nicotine produces addictive behavior by causing long-lasting changes at synapses. The long-term objective of this project is to determine how nicotine promotes long-lasting changes at synapses in the hippocampus, a brain region associated with memory formation. The behavioral and cellular effects of nicotine are mediated by its interaction with nicotinic acetylcholine receptors (nAChRs) that are normally activated by the neurotransmitter acetylcholine. When nicotine is administered systemically, it is slowly delivered to the brain where it bathes neurons for a relatively long time. Under these conditions, some nAChR subtypes are continuously activated, whereas other subtypes are inactivated by desensitization. We hypothesize that these effects of nicotine set up a condition, which promotes long-lasting changes at synapses. The specific aim of this proposed research is to determine whether continuous activation of a distinct nAChR subtype in the hippocampus during nicotine exposure modulates circuit operation to facilitate different forms of synaptic plasticity. The proposed research will be carried out using electrophysiological and optical recording techniques, as well as morphological techniques. Animals lacking a particular nAChR subtype will also be used. Results from these studies will help determine not only the cellular basis of nicotine-mediated enhancement of learning and memory, but may also aid in the development of effective treatments for long-lasting memory of nicotine abuse, by identifying a nAChR subtype involved in the effects of nicotine.